Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1993-02-01
1994-08-23
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424423, 424424, 424430, 424432, 424433, 424484, 424485, 424486, 424487, 424488, 424489, 424DIG14, 424449, 424451, 514800, 514841, 514842, 514843, A61F 202, A61F 606, A61K 3738, A61K 950
Patent
active
053405846
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to methods for inhibiting conception in mammals and for treating benign gynecological disorders, as well as to formulations for use in such methods. More particularly, the present invention is directed to methods and preparations effective in inhibiting conception and in treating benign gynecological disorders, including premenstrual syndrome, for extended periods of time.
Gonadotropin releasing hormone (GnRH), also known as luteinizing hormone releasing hormone (LHRH), produced by the hypothalamus controls the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary and thence gonadal steroid hormone production. Potent synthetic agonists of GnRH administered to premenopausal women have been shown to produce a transient rise in FSH/LH release followed by a sustained suppression. Immediately after GnRH agonists became available in the late 1970s, a number of approaches to the use of a GnRH agonist as a contraceptive were explored. Among these approaches, inhibition of ovulation by the chronic administration of GnRH agonists appeared to offer the greatest potential. It was hoped that GnRH agonists would form the basis of an improved method of contraception by offering greater convenience, increased effectiveness or fewer side effects than is the case with combination-type oral contraceptives (COCs).
Inhibition of ovulation by GnRH agonists has been found, as expected, to be dose-related. When administered in a dose just high enough to ensure anovulation, the ovaries may continue to produce estrogen. This is an unstable situation, with different women having widely varying serum estrogen levels. There has also been concern that endometrial hyperplasia would occur in some women, while in others there would be periods of hypoestrogenemia with unacceptable vasomotor symptoms and probably loss of bone mineral content.
"High-dose" GnRH agonists have been observed to uniformly reduce serum estradiol and serum progesterone to oophorectomized levels. The development of "high dose" depot formulations of GnRH agonists permits sustained inhibition of ovulation and suppression of ovarian steroid production, as well as improved ease of drug administration. The treatment is reversible; in a study of 50 patients, recovery of menstrual function occurred on average at 87 days (range 44-126 days) following 6-8 months treatment with the GnRH agonist tryptorelin [Zorn, J. -R. et al., Fertil.Steril. 53:401-06 (1990)]. Other depot formulations of GnRH agonists produce similar sex-steroid suppression including decapeptyl [George, M. et al., Int.J.Fertil. 34:19-24 (1989)], goserelin [Kaufman, M. et al., J.Clin.Oncol. 7:1113-19 (1989)] and buserelin [Donnez, J. et al., Fertil.Steril. 51:947-50 (1989)].
In spite of their clear effectiveness as contraceptive agents, side effects attendant to the use of "high-dose" GnRH agonists for prevention of pregnancy has prevented their general adoption. Common side effects reported to occur with depot GnRH agonists in premenopausal patients include: hot flashes, vaginal dryness, irregular vaginal bleeding and fatigue. Additional side effects that have been reported in some patients receiving GnRH agonists include: sweating, headache, depression, lability in mood, nausea and/or vomiting, nervousness, insomnia, pollakisuria, weight gain, sleepiness, dizziness, decreased libido and mild breast tenderness or swelling.
A recent review article reflects current thinking about GnRH and its analogues (Conn, P. M. and Crowley, Jr., W. F., "Gonadotropin-Releasing Hormone and Its Analogues," N.Engl.J.Med. 324:93-103 (1991)). The authors note at pages 96-97 that "whether to supplement GnRH-agonist analogues with sex steroids is a complex decision"; they propose estrogen replacement followed by the administration of a progestational agent "at physiologic doses and in a physiologic (i.e., sequential) pattern."
U.S. Pat. No. 4,762,717 to Crowley, Jr., the entire disclosure of which is hereby incorporated by reference, is bas
REFERENCES:
Watts et al., "Effects of Oral Estrogens and Esterified Estrogens & Androgen on Bone Mineral Density in Postmenopausal Women", The 2nd Annual Meeting North American Menopause Society Program, S-F16, Sep. 25-28, 1991.
Bergkvist, et al. N.E. Journal of Medicine 321: 293-97 (1989).
Conn et al. N.E. Journal of Medicine 324: 93-103 (1991).
Donnez et al. Fertility and Sterility 51: 947-50 (1989).
Cowsar et al. Long Acting Contraceptive Delivery Stystems pp. 145-162 (eds. Zatuchni et al. 1984).
Ferguson et al. Journal of Controlled Release 8: 45-54 (1988).
Friedman Fertility and Sterility 51: 526-28 (1989).
Garza-Flores et al. Contraception 30: 371-79 (1984).
Gilley et al. Southern Research Inst. 73-73.
Hahn et al. Long Acting Contraceptive Delivery Systems, pp. 97-112 (eds. Zatuchni et al. 1984).
Hsieh et al. Rutgers Univ. pp. 134-135.
Hsieh et al. Drug Development and Industrial Pharmacy II(6&7): 1391-1410 (1985).
Kaufmann et al. Journal of Clinical Oncology 7: 1113-1119 (1989).
Pike Malcolm C.
Spicer Darcy V.
Azpuru Carlos
Page Thurman K.
University of Southern California
LandOfFree
Methods and formulations for use in inhibiting conception and in does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods and formulations for use in inhibiting conception and in, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods and formulations for use in inhibiting conception and in will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-501288